Abused drugs produce long-lasting changes in behaviors via biochemical mechanisms that are largely unknown. Drug-altered changes in expression of specific genes in the brain can provide a major window on possible biochemical substrates for addiction. To further explore this area, we have established and developed subtracted differential display and are now increasingly focused on array hybridization techniques that has allowed identification of dozens of distinct cDNAs that correspond to candidate drug-regulated genes expressed in brain. During this year, we have enhanced characterization of candidate genes whose expression is regulated by amphetamine, cocaine and morphine and begun to compare these dta to data from knockout mice that lack major receptor sites for morphine, cocaine and amphetamine. Using microarrays, we have been able to detect good hybridizaiton signals from ca 38% of the genes sampled on 6800 gene microarrays, and to identify the 2-3% that are regulated more than 2-fold by knockouts or drugs. - differential display array hybridization NrCAM calcineurin Gbeta1 cocaine amphetamine morphine